Alpha sympathomimetic treatment of autonomic insufficiency with orthostatic hypotension

Abstract

Purpose: In this double-blind study, the authors compared the safety and efficacy of the investigational oral agent midodrine, a specific alpha 1-sympathomimetic agent, with ephedrine, a nonspecific alpha- and beta-adrenergic receptor agonist. Eight patients (4 men and 4 women) with refractory orthostatic hypotension resulting from autonomic failure were studied. This study was based on the notion that neurogenic orthostatic hypotension results from attenuation of adrenergic nerve traffic and not from alpha-adrenergic receptor dysfunction. Although arteriolar vasoconstrictors seem to be appropriate therapeutic agents, their success has been limited, and the search for an ideal drug is ongoing.

Methods: The authors employed a blocked, double-blind, randomized crossover design. The single-blind placebo run-in period was 2 days. The double-blind titration period with either midodrine or ephedrine was 3 to 5 days; the titration end point was to increase standing systolic blood pressure to > or = 80 mm Hg and to maintain a supine pressure below 180/100 mm Hg. The maintenance period was 3 to 5 days. A 4-day placebo washout period was interposed at the crossover point.

Results: The ability to stand improved in patients treated with midodrine but not with ephedrine. Midodrine significantly increased both systolic (P < 0.001) and diastolic (P < 0.001) standing blood pressure over placebo (P < 0.001) and ephedrine (P < 0.05). In contrast, ephedrine-induced changes in standing pressures did not significantly differ from placebo (P > 0.05). Midodrine treatment improved the frequency of the ability to stand as compared with ephedrine, and was associated with a significantly higher incidence of standing systolic pressures > 80 mm Hg than was placebo (P < 0.001). Both midodrine and ephedrine significantly increased supine systolic and diastolic blood pressures over placebo (P < 0.001, P < 0.01, P < 0.01, P < 0.01, respectively), but were not significantly different from each other. Ephedrine significantly increased (P < 0.05) the pulse rate as compared with placebo and midodrine, whereas midodrine produced a statistically significant (P < 0.05) but clinically minimal decrease in pulse rate compared with placebo. Neither drug affected clinical laboratory variables.

Conclusions: Midodrine safely and effectively improved orthostatic hypotension caused by autonomic failure. Our data suggest that the ability to stand is improved better by midodrine than by ephedrine.